SplicerAV: a tool for mining microarray expression data for changes in RNA processing.
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BACKGROUND: Over the past two decades more than fifty thousand unique clinical and biological samples have been assayed using the Affymetrix HG-U133 and HG-U95 GeneChip microarray platforms. This substantial repository has been used extensively to characterize changes in gene expression between biological samples, but has not been previously mined en masse for changes in mRNA processing. We explored the possibility of using HG-U133 microarray data to identify changes in alternative mRNA processing in several available archival datasets. RESULTS: Data from these and other gene expression microarrays can now be mined for changes in transcript isoform abundance using a program described here, SplicerAV. Using in vivo and in vitro breast cancer microarray datasets, SplicerAV was able to perform both gene and isoform specific expression profiling within the same microarray dataset. Our reanalysis of Affymetrix U133 plus 2.0 data generated by in vitro over-expression of HRAS, E2F3, beta-catenin (CTNNB1), SRC, and MYC identified several hundred oncogene-induced mRNA isoform changes, one of which recognized a previously unknown mechanism of EGFR family activation. Using clinical data, SplicerAV predicted 241 isoform changes between low and high grade breast tumors; with changes enriched among genes coding for guanyl-nucleotide exchange factors, metalloprotease inhibitors, and mRNA processing factors. Isoform changes in 15 genes were associated with aggressive cancer across the three breast cancer datasets. CONCLUSIONS: Using SplicerAV, we identified several hundred previously uncharacterized isoform changes induced by in vitro oncogene over-expression and revealed a previously unknown mechanism of EGFR activation in human mammary epithelial cells. We analyzed Affymetrix GeneChip data from over 400 human breast tumors in three independent studies, making this the largest clinical dataset analyzed for en masse changes in alternative mRNA processing. The capacity to detect RNA isoform changes in archival microarray data using SplicerAV allowed us to carry out the first analysis of isoform specific mRNA changes directly associated with cancer survival.
Gene Expression Profiling
Oligonucleotide Array Sequence Analysis
Published Version (Please cite this version)10.1186/1471-2105-11-108
Publication InfoRobinson, Timothy J; Dinan, Michaela A; Dewhirst, Mark; Garcia-Blanco, Mariano A; & Pearson, James L (2010). SplicerAV: a tool for mining microarray expression data for changes in RNA processing. BMC Bioinformatics, 11. pp. 108. 10.1186/1471-2105-11-108. Retrieved from https://hdl.handle.net/10161/4332.
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Gustavo S. Montana Distinguished Professor Emeritus of Radiation Oncology
Mark W. Dewhirst, DVM, PhD is the Gustavo S. Montana Professor of Radiation Oncology and Vice Director for Basic Science in the Duke Cancer Institute. Dr. Dewhirst has research interests in tumor hypoxia, angiogenesis, hyperthermia and drug transport. He has spent 30 years studying causes of tumor hypoxia and the use of hyperthermia to treat cancer. In collaboration with Professor David Needham in the Pratt School of Engineering, he has developed a novel thermally sensitive drug carrying liposom
Associate Professor in Population Health Sciences
Dr. Dinan is a health services researcher with a focus on emerging medical technology in cancer. Dr. Dinan currently holds an AHRQ K99/R00 pathway to independence award to examine adoption of Oncotype DX molecular testing in breast cancer and has conducted work in breast and other cancers examining emerging technologies and their associated disparities in utilization, outcomes and costs. Dr. Dinan has expertise in both secondary data analysis and clinical registry methodologies. Her secondary
Adjunct Professor in the Molecular Genetics and Microbiology
Human and viral genes are complex genetic units of information that are tightly regulated. The laboratory studies three aspects of this regulation: the interface between synthesis of mammalian messenger RNAs and the processing events required to mature these transcripts, the alternative processing of these messenger RNAs to produce multiple proteins from one gene, and the regulation of gene expression in human pathogenic flaviviruses. In the great majority of human transcripts
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